IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:135

Article

Niss, Omar¹  Sholl, Allyson²  Bleesing, Jack J.¹  Hildeman, David A.² 

[1] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA

关键词: ALPS;    Bim;    Bcl-2 pathway;    IL-10;    BH3 mimetic;    ABT-737;    T cell homeostasis;    double negative T cells;    apoptosis;   

DOI  :  10.1016/j.jaci.2014.07.020

来源: Elsevier

【 摘 要 】

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder of T cell homeostasis caused by mutations that impair FAS-mediated apoptosis. A defining characteristic of ALPS is the expansion of double negative T cells (DNTC). Relatively little is known about how defective FAS-driven cell death and the Bcl-2 apoptotic pathway intersect in ALPS patients. Objective: We studied changes in Bcl-2 family member expression in ALPS to determine whether the Bcl-2 pathway might provide a therapeutic target. Methods: We used flow cytometry to analyze the expression of pro-and anti-apoptotic Bcl-2 family members in T cells from 12 ALPS patients and determined the in vitro sensitivity of ALPS DNTC to the pro-apoptotic BH3 mimetic, ABT-737. Results: The pro-apoptoticmolecule, Bim, was significantly elevated in DNTC. Although no general pattern of individual anti-apoptotic Bcl-2 family members emerged, increased expression of Bim was always accompanied by increased expression of at least 1 anti-apoptotic Bcl-2 family member. Strikingly, Bim levels in DNTC correlated significantly with serum IL-10 in ALPS patients, and IL-10 was sufficient to mildly induce Bim in normal and ALPS T cells via a Janus kinase/signal transducer and activator of transcription 3-dependent mechanism. Finally, ABT-737 preferentially killed ALPS DNTC in vitro. Conclusion: Combined, these data show that an IL-10/Janus kinase/signal transducer and activator of transcription 3 pathway drives Bim expression in ALPS DNTC, which renders them sensitive to BH3 mimetics, uncovering a potentially novel therapeutic approach to ALPS.

【 授权许可】

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